PROJECT SUMMARY Head and neck squamous cell carcinoma (HNSCC) is associated with poor survival despite therapeutic advances. We previously reported that cancer-associated fibroblasts (CAFs) facilitate tumor growth and metastasis. In addition, we reported a higher rate of secretory autophagy in CAFs that is associated with secretion of tumor promoting factors. In preliminary studies, we demonstrate that signaling in CAFs results in activation of STAT3, which in turn then activates SOX2. This suppresses mTOR signaling and induces secretory autophagy. The consequence of this autophagic process is the secretion of various cytokines and chemokines, which in turn affects HNSCC. Based on these data, we hypothesize that secretory autophagy in CAFs results in cytokine release that facilitates HNSCC growth and impacts response to therapy. We will test this hypothesis in 3 Specific Aims. In Aim 1, we will elucidate the mechanism of secretory autophagy in fibroblasts. In Aim 2, we will characterize the role of CAF-secretory autophagy on HNSCC. Finally, in Aim 3, we will determine the therapeutic potential of mitigating autophagy. These studies are significant in that they will help elucidate the role of stromal autophagy in tumor progression and enable the development of more effective therapeutic approaches for HNSCC.